Carboxylic acid derivatives, their preparation and their use

ABSTRACT

Carboxylic acid derivatives of the formula I ##STR1## here R 1  is a tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the meaning explained in the description.

This application is a 371 or PCT/EP96/03793, filed Aug. 29, 1996.

The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. Endothelin or ET hereinafter indicates one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to diseases. As reported in the literature, elevated levels of endothelin in plasma have been found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990)).

Accordingly, substances which specifically inhibit the binding of endothelin to the receptor should also antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.

It has been found (WO 94/02474) that certain carboxylic acid derivatives with the general formula Q are good inhibitors of endothelin receptors ##STR2##

However, this related mainly to compounds with a double bond in the molecule. Besides R^(A) and R^(B), a maximum of one hydrogen atom is permitted on the β center.

It has now been found, surprisingly, that this hydrogen atom can be replaced by alkyl radicals. This results in a quaternary β center with, at the same time, a large increase in the activity with regard to endothelin receptors (see Examples).

The invention relates to carboxylic acid derivatives of the formula I ##STR3## where R¹ is a tetrazole [sic], nitrile [sic], COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:

R² and R³ (which can be identical or different):

phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, cyano, NO₂ hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino, benzyloxy, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino; or

phenyl or naphthyl which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, or an oxygen or sulfur atom;

R⁴ phenyl or naphthyl, methylenedioxyphenyl, ethylenedioxyphenyl, indanyl, indolyl, pyridyl, benzopyranyl, furanyl, benzofuranyl, isooxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyrimidinyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, C₃ -C₇ -cycloalkyl, thienyl, oxazolyl, thiazolyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, NO₂, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino, benzyloxy, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino, it being possible for the alkyl radicals together to form a ring;

R⁵ C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino;

phenyl, benzyl, 1-methylnaphthyl, 2-methylnaphthyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, phenoxy, C₁ -C₄ -alkylthio, dioxomethylene [sic] or dioxoethylene [sic];

n 1-2.

The compounds, and the intermediates for preparing them, such as Va, may have one or more asymmetric substituted carbon atoms. Compounds of this type may be in the form of pure enantiomers or pure diastereomers or of a mixture thereof. The use of an enantiomerically pure compound as agent is preferred.

The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors of endothelin receptors.

Compounds of the formula I can be prepared by initially reacting a ketone of type II with a phosphono ester of the formula III in the presence of a base to give compounds of the formula IV ##STR4##

Aprotic polar solvents such as DMF or TRF are used as solvent.

It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium, an alkali metal alcoholate such as sodium ethanolate or potassium tert-butanolate or an alkali metal amide such as lithium diisopropylamide.

The reaction is preferably carried out at a temperature in the range from 0° C. to the boiling point of the solvent or solvent mixture.

The compounds of type IV can then be reacted with aromatic compounds in the presence of a catalyst to give carboxylic acid derivatives of the general formula Va ##STR5##

Suitable catalysts for this are strong inorganic acids and Lewis acids. Examples thereof are, inter alia, sulfuric acid, aluminum trichloride, zinc chloride or iron trichloride. When sulfuric acid is used, the free acid can be obtained directly.

Alternatively, symmetrical carboxylic acid derivatives of the formula Vb can be prepared from a β-dicarbonyl compound VI and an aromatic compound in the presence of a catalyst. ##STR6##

Suitable catalysts for this are strong inorganic acids and Lewis acids. Examples thereof are, inter alia, sulfuric acid, aluminum trichloride, zinc chloride or iron trichloride (see also: Gogte G. R. et al., J. Univ. Bombay, Sect. A, 27, 1958, 41).

Another possibility for preparing compounds of type Va can start from a ketone VII ##STR7## which can be reacted with Meldrum's acid in the presence of a base such as pyridine or sodium hydride to give compounds of type VIII ##STR8##

Reaction of compounds of type VIII in diethyl ether with a Grignard reagent of the general formula IX

    R.sup.3 --Mg Y (IX)

    Y═Br, Cl, I                                            (IX)

results in compounds of type X ##STR9## in which case it may be advantageous to use in addition copper salts such as copper chloride, copper bromide, copper iodide or copper cyanide and for a Lewis acid such as trimethylsilyl chloride or boron trifluoride etherate to be present.

Hydrolysis of compounds of the formula X with mineral acids such as hydrochloric acid or sulfuric acid can then afford the compounds Va (R═OH).

Further possibilities for preparing compounds Va are similar to the methods of Zimmermann H. E. et al. J. Am. Chem, Soc. 83 (1961) 1196 or Yu A.J. et al. J. Org. Chem. 23 (1958) 1004.

Compounds of the formula Va,b can be converted into the anion (or dianion for R═H) with a strong base such as butyllithium or lithium diisopropylamide in an inert solvent such as diethyl ether or tetrahydrofuran and under inert gas, eg. nitrogen or argon, at -78° C. to room temperature. This anion reacts with alkylating agents of type VII at -78° C. to room temperature.

Quenching with concentrated NH₄ Cl or dilute mineral acid such as HCl results in compounds of the formula I ##STR10##

Compounds of type I with R¹ =tetrazole [sic] can be synthesized starting from the carboxylic acids I (R¹ ═COOH). To do this, the carboxylic acid is reacted with thionyl chloride at room temperature to give the acid chloride, which is then reacted with aqueous ammonia solution to give the amide of the formula XII. ##STR11##

Amides of the formula XII can be reacted with oxalyl chloride or phosphorus oxychloride or trifluoroacetic anhydride in DMF or pyridine at 0° C. to room temperature to give nitriles of the formula XIII ##STR12##

Reaction of nitriles of the formula XIII with sodium azide or trimethylsilyl azide in a suitable solvent such as dimethylformamide, tetrahydrofuran or 1-methyl-2-pyrrolidinone in the presence of a catalyst such as ammonium chloride (see also: Bernsteim P. R. et al., Synthesis, 1987, 1133) at room temperature or elevated temperature affords the tetrazoles XIV ##STR13##

Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R¹ ═COOH, and converting these initially in a conventional way into an activated form such as an acid halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR. This reaction can be carried out in conventional solvents and often requires the addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.

Compounds of the formula I can also be prepared by starting from salts of the corresponding carboxylic acids, ie. from compounds of the formula I where R¹ is COR and R is OM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R-A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine, or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R-A with a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction can be carried out in the usual solvents and is advantageously carried out with the addition of a base, in which case those mentioned above are suitable.

Enantiomerically pure compounds of the formula I can be obtained by carrying out with racemic or diastereomeric compounds of the formula VI a classical racemate resolution with suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, cinchonidine, cinchonine, yohimbine, morphine, dehydroabietylamine, ephedrine (-), (+), deoxyephedrine (-) (+) threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (-) , (+), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (-) threo-2-amino-1-phenyl-1,3-propanediol (+), (-) α-methylbenzylamine (+), (-) , α-(1-naphthyl)ethylamine (+), (-) α-(2-naphthyl)ethylamine (+), (-) , aminomethylpinane, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives and peptide derivatives.

Wide variation is possible in the radical R¹ in formula I. For example, R¹ is a group ##STR14## where R has the following meanings: a) a succinylimidoxy [sic] group;

b) a 5-membered heteroaromatic radical which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, and which can carry one or two halogen atoms, especially fluorine and chlorine, and/or one or two of the following radicals:

C₁ -C₄ -alkyl such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;

C₁ -C₄ -haloalkyl, especially C₁ -C₂ -haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl;

C₁ -C₄ -haloalkoxy, especially C₁ -C₂ -haloalkoxy such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 252,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy and pentafluoroethoxy, especially trifluoromethoxy;

C₁ -C₄ -alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, especially methoxy, ethoxy, 1-methylethoxy;

C₁ -C₄ -alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, especially methylthio and ethylthio;

c) R furthermore a radical ##STR15## where m is 0 or 1 and R⁶ and R⁷, which can be identical or different, have the following meanings:

hydrogen

C₁ C₈ -alkyl, especially C₁ -C₄ -alkyl as mentioned above;

C₃ -C₆ -alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, especially 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl;

C₃ -C₆ -alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl, especially 2-propynyl

C₃ -C₈ -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, it being possible for these alkyl, cycloalkyl, alkenyl and alkynyl groups each to carry one to five halogen atoms, especially fluorine or chlorine, and/or one or two of the following groups:

C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy as mentioned above, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkenylthio, C₃ -C₆ -alkynyloxy, C₃ -C₆ -alkynylthio, with the alkenyl and alkynyl constituents in these radicals preferably corresponding to the abovementioned meanings;

C₁ -C₄ -alkylcarbonyl such as, in particular, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl;

C₁ -C₄ -alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, 1,1-dimethylethoxycarbonyl;

C₃ -C₆ -alkenylcarbonyl, C₃ -C₆ -alkynylcarbonyl, C₃ -C₆ -alkenyloxycarbonyl and C₃ -C₆ -alkynyloxycarbonyl, where the alkenyl and alkynyl radicals are preferably defined as specifically stated above;

phenyl, unsubstituted or mono- or polysubstituted, eg. mono- to trisubstituted, by halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl;

di-C₁ -C₄ -alkylamino such as, in particular, dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-Isopropyl-N-methylamino, N-isopropyl-N-ethylamino, N-Isopropyl-N-propylamino;

R⁶ and R⁷ furthermore phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁ -C₄ -Alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, as mentioned above in particular;

or R⁶ and R⁷ together form a C₄ -C₇ -alkylene chain which is closed to form a ring, is unsubstituted or substituted, eg. by C₁ -C₄ -alkyl, and which may contain a heteroatom selected from the group of oxygen, sulfur or nitrogen, such as --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₆ --, --(CH₂)₇ --, --(CH₂)₂ --O--)CH₂)₂ --, --CH₂ --S--(CH₂)₃ --, --(CH₂)₂ --O--(CH₂)₃ --, --NH--(CH₂)₃ --, --CH₂ --NH--(CH₂)₂ --, --CH₂ --CH=CH--CH₂ --, --CH═CH--(CH₂) 3--;

d) R furthermore a group ##STR16## where k is 0, 1 and 2, p is 1, 2, 3 and 4, and R⁸ is C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or unsubstituted or substituted phenyl, such as mentioned above in particular.

e) R furthermore a radical OR⁹ where R⁹ is:

hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium, or an environmentally compatible organic ammonium ion such as tertiary C₁ -C₄ -alkylammonium or the ammonium ion;

C₃ -C₈ -cycloalkyl as mentioned above, which can carry one to three C₁ -C₄ -alkyl groups;

C₁ -C₈ -alkyl such as, in particular, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,l-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,I-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, which can carry one to five halogen atoms, in particular fluorine and chlorine, and/or one of the following radicals:

C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, cyano, C₁ -C₄ -alkylcarbonyl, C₃ -C₈ -cycloakyl, C₁ 1∝C₄ -alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, where the aromatic radicals in turn can each carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio, as mentioned above in particular;

C₁ -C₈ -alkyl as mentioned above, which can carry one to five halogen atoms, in particular fluorine and/or chlorine, and carries one of the following radicals: a 5-membered heteroaromatic radical containing one to three nitrogen atoms, or a 5-membered heteroaromatic radical containing one nitrogen atom and one oxygen or sulfur atom, which can carry one to four halogen atoms and/or one or two of the following radicals:

nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 3-ethyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 3-tert-butyl-5-isoxazolyl;

C₂ -C₆ -alkyl which has in position 2 one of the following radicals: C₁ -C₄ -alkoxyimino, C₃ -C₆ -alkynyloxyimino, C₃ -C₆ -haloalkenyloxyimino or benzyloxyimino;

C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl, it being possible for these groups in turn to carry one to five halogen atoms;

R⁹ furthermore a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio, as mentioned above in particular;

a 5-membered heteroaromatic radical which is linked via a nitrogen atom and contains one to three nitrogen atoms and which can carry one or two halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;

R⁹ furthermore a group ##STR17## where R¹⁰ and R¹¹, which can be identical or different, are: C₁ -CS-alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -Cycloalkyl, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or an unsubstituted or substituted phenyl radical, as mentioned above in particular;

phenyl, which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, where these radicals correspond in particular to those mentioned above;

or R¹⁰ and R¹¹ together form a C₃ -C₁₂ -alkylene chain which can carry one to three C₁ -C₄ -alkyl groups and contain a heteroatom from the group of oxygen, sulfur and nitrogen, as mentioned in particular for R6 and R⁷.

f) R furthermore a radical ##STR18## where R¹² is: C₁ -C₄ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl as mentioned above in particular, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or a phenyl radical as mentioned above;

phenyl, unsubstituted or substituted, in particular as mentioned above.

g) R a radical ##STR19## where R¹² has the abovementioned meanings. R¹ can furthermore be:

tetrazole [sic] or nitrile [sic].

With a view to the biological effect, preferred carboxylic acid derivatives of the general formula I, both as pure enantiomers and pure diastereomers and as mixtures thereof, are those where the substituents have the following meanings:

R¹ tetrazole [sic], COOH or a radical which can be hydrolyzed to COOH;

R² and R³ (which can be identical or different);

phenyl or naphthyl which can be substituted by one or more of the following radicals: F, Cl, Br, I, cyano, NO₂, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyloxy, phenoxy, methylthio, ethylthio, benzyloxy, amino, methylamino, dimethylamino;

R⁴ phenyl, methylenedioxyphenyl, ethylenedioxyphenyl, indanyl, pyridyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzothienyl, 2-pyrimidinyl, 4-pyrimidinyl, 2,3-dihydrobenzothienyl, each of which can be substituted by one or more of the following radicals: F, Cl, Br, I, cyano, NO₂, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, tert-butyloxy, trifluoromethyloxy, phenoxy, methylthio, ethylthio, propylthio, benzyloxy, amino, methylamino, dimethylamino;

R⁵ methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, tert-butyl, pentyl, 3-methylbutyl, hexyl, 3-pentyl, 4-methylpentyl, 2-ethylbutyl, each of which can be substituted one or more times by: cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, dimethylamino;

allyl, vinyl, trifluoromethyl, 2,2,2-trifluoroethyl;

phenyl, benzyl, each of which can be substituted by one or is more of the following radicals: F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, dioxomethylene [sic], dioxoethylene [sic];

n 1-2

Examples of preferred compounds are listed in the following Table:

    __________________________________________________________________________       #STR20##                                                                     No.                                                                               R  R.sup.2     R.sup.3     R.sup.5                                                                               R.sup.4            n                      __________________________________________________________________________      1 OH Phenyl      Phenyl      Methyl Phenyl             1                         2 OH Phenyl Phenyl Methyl 3,5-Dimethylphenyl 1                                 3 OH Phenyl Phenyl Methyl 3,5-Dimethoxyphenyl 1                                4 OH Phenyl Phenyl Methyl 3,4-Methylenedioxyphenyl 1                           5 OH Phenyl Phenyl Methyl 2,3-Dihydro-benzofuran-5-yl 1                        6 OH Phenyl Phenyl Methyl 2,3-Dihydro-1H-inden-5-yl 1                          7 OH Phenyl Phenyl Methyl 3-Methoxy-5-methylphenyl 1                           8 OH Phenyl Phenyl Methyl 3,4-Ethylenedioxyphenyl 1                            9 OH Phenyl Phenyl Methyl 5-Methoxy-3,4-methylenedioxyphenyl 1                                                                        10 OH Phenyl                                                                 Phenyl Methyl                                                                  3,5-Diethylphenyl                                                              1                         11 OH Phenyl Phenyl Methyl 3,4-Dimethoxyphenyl 1                               12 OH Phenyl Phenyl Methyl 3-Methyl-4-benzyloxyphenyl 1                        13 OH Phenyl Phenyl Methyl 3-Benzyloxy-5-methoxyphenyl 1                       14 OH Phenyl Phenyl Methyl 3-Benzyloxy-4-methoxyphenyl 1                       15 OH Phenyl Phenyl Methyl 3-Hydroxy-4-methoxyphenyl 1                         16 OH Phenyl Phenyl Methyl 4-Hydroxy-3-methoxyphenyl 1                         17 OH Phenyl Phenyl Methyl 3,5-Bis-(trifluoromethyl)-phenyl 1                  18 OH Phenyl Phenyl Methyl 3-Methylphenyl 1                                    19 OH Phenyl Phenyl Methyl 3-Methoxyphenyl 1                                   20 OH Phenyl Phenyl Methyl 4-Benzyloxyphenyl 1                                 21 OH Phenyl Phenyl Methyl 4-Phenoxyphenyl                                     22 OH Phenyl Phenyl Methyl 6-Methylpyridin-2-yl 1                              23 OH Phenyl Phenyl Methyl 6-Ethylpyridin-2-yl 1                               24 OH Phenyl Phenyl Methyl 6-Methoxypyridin-2-yl 1                             25 OH Phenyl Phenyl Methyl 4,6-Dimethylpyridin-2-yl 1                          26 OH Phenyl Phenyl Methyl 4,6-Diethylpyridin-2-yl 1                           27 OH Phenyl Phenyl Methyl 4-Methyl-6-methoxypyridin-2-yl 1                    28 OH Phenyl Phenyl Methyl 6,7-Dihydro-5H-cyclopenta[b]pyridin-2-yl 1                                                                 29 OH Phenyl                                                                 Phenyl Methyl                                                                  4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                       30 OH Phenyl                                                                 Phenyl Methyl                                                                  4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                 31 OH Phenyl                                                                 Phenyl Methyl                                                                  4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                      32 OH Phenyl                                                                 Phenyl Methyl                                                                  4,6-Diethylpyrimid                                                             in-2-yl 1                                                                        33 OH Phenyl                                                                 Phenyl Methyl                                                                  6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                     34 OH Phenyl Phenyl Methyl Naphth-2-yl 1                                       35 OH Phenyl Phenyl Methyl 6,7-Dihydro-5H-cyclopenta[c]pyridin-2-yl 1                                                                 36 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl Phenyl                                                              1                         37 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 3,5-Dimethylphenyl 1                                                                     38 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3,5-Dimethoxypheny                                                             l 1                       39 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 3,4-Methylenedioxyphenyl                                                               1                         40 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 2,3-Dihydro-benzofuran-5-y                                                             l 1                       41 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 2,3-Dihydro-1H-inden-5-yl                                                              1                         42 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 3-Methoxy-5-methylphenyl                                                               1                         43 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 3,4-Ethylenedioxyphenyl 1         44 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 5-Methoxy-3,4-methylenedio                                                             xyphenyl 1                                                                       45 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3,5-Diethylphenyl                                                              1                         46 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 3,4-Dimethoxyphenyl 1                                                                    47 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3-Methyl-4-benzylo                                                             xyphenyl 1                                                                       48 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3-Benzyloxy-5-meth                                                             oxyphenyl 1                                                                      49 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3-Benzyloxy-4-meth                                                             oxyphenyl 1                                                                      50 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3-Hydroxy-4-methox                                                             yphenyl 1                                                                        51 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4-Hydroxy-3-methox                                                             yphenyl 1                                                                        52 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                 53 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3-Methylphenyl 1                                                                 54 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     3-Methoxyphenyl 1         55 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 4-Benzyloxyphenyl 1                                                                      56 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4-Phenoxyphenyl 1         57 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 6-Methylpyridin-2-yl 1                                                                   58 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     6-Ethylpyridin-2-y                                                             l 1                       59 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 6-Methoxypyridin-2-yl 1                                                                  60 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4,6-Dimethylpyridi                                                             n-2-yl 1                  61 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 4,6-Diethylpyridin-2-yl 1         62 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 4-Methyl-6-methoxypyridin-                                                             2-yl 1                    63 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 6,7-Dihydro-5H-cyclopenta[                                                             b]pyridin-2-yl 1                                                                 64 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                       65 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                 66 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                      67 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     4,6-Diethylpyrimid                                                             in-2-yl 1                                                                        68 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Methyl                                                                     6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                     69 OH p-Methoxyphenyl p-Methoxyphenyl Methyl Naphth-2-yl                       70 OH p-Methoxyphenyl p-Methoxyphenyl Methyl 6,7-Dihydro-5H-cyclopenta[                                                             c]pyridin-2-yl 1                                                                 71 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl Phenyl 1         72 OH p-Methylphenyl p-Methylphenyl Methyl 3,5-Dimethylphenyl 1                                                                       73 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 3,5-Dimet                                                             hoxyphenyl 1                                                                     74 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 3,4-Methy                                                             lenedioxyphenyl 1         75 OH p-Methylphenyl p-Methylphenyl Methyl 2,3-Dihydro-benzofuran-5-yl                                                              1                         76 OH p-Methylphenyl p-Methylphenyl Methyl 2,3-Dihydro-1H-inden-5-yl 1         77 OH p-Methylphenyl p-Methylphenyl Methyl 3-Methoxy-5-methylphenyl 1                                                                 78 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 3,4-Ethyl                                                             enedioxyphenyl 1                                                                 79 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 5-Methoxy                                                             -3,4-methylenediox                                                             yphenyl 1                                                                        80 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 3,5-Dieth                                                             ylphenyl 1                                                                       81 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 3,4-Dimet                                                             hoxyphenyl 1                                                                     82 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 3-Methyl-                                                             4-benzyloxyphenyl                                                              1                         83 OH p-Methylphenyl p-Methylphenyl Methyl 3-Benzyloxy-5-methoxyphenyl                                                              1                         84 OH p-Methylphenyl p-Methylphenyl Methyl 3-Benzyloxy-4-methoxyphenyl                                                              1                         85 OH p-Methylphenyl p-Methylphenyl Methyl 3-Hydroxy-4-methoxyphenyl 1         86 OH p-Methylphenyl p-Methylphenyl Methyl 4-Hydroxy-3-methoxyphenyl 1         87 OH p-Methylphenyl p-Methylphenyl Methyl 3,5-Bis-(trifluoromethyl)-ph                                                             enyl 1                    88 OH p-Methylphenyl p-Methylphenyl Methyl 3-Methylphenyl 1                    89 OH p-Methylphenyl p-Methylphenyl Methyl 3-Methoxyphenyl 1                   90 OH p-Methylphenyl p-Methylphenyl Methyl 4-Benzyloxyphenyl 1                                                                        91 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 4-Phenoxy                                                             phenyl 1                  92 OH p-Methylphenyl p-Methylphenyl Methyl 6-Methylpyridin-2-yl 1                                                                     93 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 6-Ethylpy                                                             ridin-2-yl 1                                                                     94 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 6-Methoxy                                                             pyridin-2-yl 1                                                                   95 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 4,6-Dimet                                                             hylpyridin-2-yl 1         96 OH p-Methylphenyl p-Methylphenyl Methyl 4,6-Diethylpyridin-2-yl 1                                                                  97 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 4-Methyl-                                                             6-methoxypyridin-2                                                             -yl 1                     98 OH p-Methylphenyl p-Methylphenyl Methyl 6,7-Dihydro-5H-cyclopenta[b]                                                             pyridin-2-yl 1                                                                   99 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl 4,6-Dimet                                                             hylpyrimidin-2-yl                                                              1                        100 OH p-Methylphenyl p-Methylphenyl Methyl 4-Methoxy-6-methylpyrimidin-                                                             2-yl 1                   101 OH p-Methylphenyl p-Methylphenyl Methyl 4,6-Dimethoxypyrimidin-2-yl                                                              1                        102 OH p-Methylphenyl p-Methylphenyl Methyl 4,6-Diethylpyrimidin-2-yl 1        103 OH p-Methylphenyl p-Methylphenyl Methyl 6,7-Dihydro-5H-cyclopentapyr                                                             imidin-2-yl 1                                                                   104 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Methyl Naphth-2-                                                             yl 1                     105 OH p-Methylphenyl p-Methylphenyl Methyl 6,7-Dihydro-5H-cyclopenta[c]                                                             pyridin-2-yl 1                                                                  106 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  Phenyl 1                 107 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3,5-Dimethylphenyl                                                              1                       108 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3,5-Dimethoxypheny                                                             l 1                      109 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3,4-Methylenedioxy                                                             phenyl 1                 110 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      2,3-Dihydro-benzof                                                             uran-5-yl 1                                                                     111 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  2,3-Dihydro-1H-ind                                                             en-5-yl 1                                                                       112 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3-Methoxy-5-methyl                                                             phenyl 1                 113 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3,4-Ethylenedioxyp                                                             henyl 1                  114 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      5-Methoxy-3,4-meth                                                             ylenedioxyphenyl                                                               1                        115 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3,5-Diethylphenyl                                                              1                        116 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3,4-Dimethoxypheny                                                             l 1                      117 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      3-Methyl-4-benzylo                                                             xyphenyl 1                                                                      118 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3-Benzyloxy-5-meth                                                             oxyphenyl 1                                                                     119 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3-Benzyloxy-4-meth                                                             oxyphenyl 1                                                                     120 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3-Hydroxy-4-methox                                                             yphenyl 1                                                                       121 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  4-Hydroxy-3-methox                                                             yphenyl 1                                                                       122 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                123 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3-Methylphenyl 1                                                                124 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  3-Methoxyphenyl 1        125 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      4-Benzyloxyphenyl                                                              1                        126 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      4-Phenoxyphenyl 1        127 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      6-Methylpyridin-2-                                                             yl 1                     128 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      6-Ethylpyridin-2-y                                                             l 1                      129 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      6-Methoxypyridin-2                                                             -yl 1                    130 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      4,6-Dimethylpyridi                                                             n-2-yl 1                 131 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      4,6-Diethylpyridin                                                             -2-yl 1                  132 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  133 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   134 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                      135 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                136 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     137 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       138 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    139 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Methyl                                                                      Naphth-2-yl 1                                                                   140 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Methyl                                                                  6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   141 OH Phenyl Phenyl Ethyl Phenyl 1                                            142 OH Phenyl Phenyl Ethyl 3,5-Dimethylphenyl 1                                143 OH Phenyl Phenyl Ethyl 3,5-Dimethoxyphenyl 1                               144 OH Phenyl Phenyl Ethyl 3,4-Methylenedioxyphenyl 1                          145 OH Phenyl Phenyl Ethyl 2,3-Dihydro-benzofuran-5-yl 1                       146 OH Phenyl Phenyl Ethyl 2,3-Dihydro-1H-inden-5-yl 1                         147 OH Phenyl Phenyl Ethyl 3-Methoxy-5-methylphenyl 1                          148 OH Phenyl Phenyl Ethyl 3,4-Ethylenedioxyphenyl 1                           149 OH Phenyl Phenyl Ethyl 5-Methoxy-3,4-methylenedioxyphenyl 1                                                                       150 OH Phenyl                                                                 Phenyl Ethyl                                                                   3,5-Diethylphenyl                                                              1                        151 OH Phenyl Phenyl Ethyl 3,4-Dimethoxyphenyl 1                               152 OH Phenyl Phenyl Ethyl 3-Methyl-4-benzyloxyphenyl 1                        153 OH Phenyl Phenyl Ethyl 3-Benzyloxy-5-methoxyphenyl 1                       154 OH Phenyl Phenyl Ethyl 3-Benzyloxy-4-methoxyphenyl 1                       155 OH Phenyl Phenyl Ethyl 3-Hydroxy-4-methoxyphenyl 1                         156 OH Phenyl Phenyl Ethyl 4-Hydroxy-3-methoxyphenyl 1                         157 OH Phenyl Phenyl Ethyl 3,5-Bis-(trifluoromethyl)-phenyl 1                  158 OH Phenyl Phenyl Ethyl 3-Methylphenyl 1                                    159 OH Phenyl Phenyl Ethyl 3-Methoxyphenyl 1                                   160 OH Phenyl Phenyl Ethyl 4-Benzyloxyphenyl 1                                 161 OH Phenyl Phenyl Ethyl 4-Phenoxyphenyl 1                                   162 OH Phenyl Phenyl Ethyl 6-Methylpyridin-2-yl 1                              163 OH Phenyl Phenyl Ethyl 6-Ethylpyridin-2-yl 1                               164 OH Phenyl Phenyl Ethyl 6-Methoxypyridin-2-yl 1                             165 OH Phenyl Phenyl Ethyl 4,6-Dimethylpyridin-2-yl 1                          166 OH Phenyl Phenyl Ethyl 4,6-Diethylpyridin-2-yl 1                           167 OH Phenyl Phenyl Ethyl 4-Methyl-6-methoxypyridin-2-yl 1                    168 OH Phenyl Phenyl Ethyl 6,7-Dihydro-5H-cyclopenta[b]pyridin-2-yl 1                                                                 169 OH Phenyl                                                                 Phenyl Ethyl                                                                   4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                      170 OH Phenyl                                                                 Phenyl Ethyl                                                                   4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                171 OH Phenyl                                                                 Phenyl Ethyl                                                                   4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     172 OH Phenyl                                                                 Phenyl Ethyl                                                                   4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       173 OH Phenyl                                                                 Phenyl Ethyl                                                                   6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    174 OH Phenyl Phenyl Ethyl Naphth-2-yl 1                                       175 OH Phenyl Phenyl Ethyl 6,7-Dihydro-5H-cyclopenta[c]pyridin-2-yl 1                                                                 176 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl Phenyl                                                               1                        177 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3,5-Dimethylphenyl 1                                                                     178 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      3,5-Dimethoxypheny                                                             l 1                      179 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3,4-Methylenedioxyphenyl 1        180 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 2,3-Dihydro-benzofuran-5-yl                                                              1                       181 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 2,3-Dihydro-1H-inden-5-yl                                                               1                        182 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Methoxy-5-methylphenyl 1        183 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3,4-Ethylenedioxyphenyl 1                                                                184 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      5-Methoxy-3,4-meth                                                             ylenedioxyphenyl                                                               1                        185 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3,5-Diethylphenyl 1                                                                      186 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      3,4-Dimethoxypheny                                                             l 1                      187 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Methyl-4-benzyloxyphenyl                                                              1                        188 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Benzyloxy-5-methoxyphenyl                                                              1                       189 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Benzyloxy-4-methoxyphenyl                                                              1                       190 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Hydroxy-4-methoxyphenyl                                                               1                        191 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4-Hydroxy-3-methoxyphenyl                                                               1                        192 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3,5-Bis-(trifluoromethyl)-p                                                             henyl 1                  193 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Methylphenyl 1                  194 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 3-Methoxyphenyl 1                 195 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4-Benzyloxyphenyl 1                                                                      196 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      4-Phenoxyphenyl 1        197 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 6-Methylpyridin-2-yl 1                                                                   198 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      6-Ethylpyridin-2-y                                                             l 1                      199 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 6-Methoxypyridin-2-yl 1                                                                  200 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      4,6-Dimethylpyridi                                                             n-2-yl 1                 201 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4,6-Diethylpyridin-2-yl 1                                                                202 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  203 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   204 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4,6-Dimethylpyrimidin-2-yl                                                              1                        205 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4-Methoxy-6-methylpyrimidin                                                             -2-yl 1                  206 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4,6-Dimethoxypyrimidin-2-yl                                                              1                       207 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 4,6-Diethylpyrimidin-2-yl                                                               1                        208 OH p-Methoxyphenyl p-Methoxyphenyl Ethyl 6,7-Dihydro-5H-cyclopentapy                                                             rimidin-2-yl 1                                                                  209 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      Naphth-2-yl 1                                                                   210 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Ethyl                                                                      6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   211 OH p-Methylphenyl p-Methylphenyl Ethyl Phenyl 1                            212 OH p-Methylphenyl p-Methylphenyl Ethyl 3,5-Dimethylphenyl 1                                                                       213 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 3,5-Dimeth                                                             oxyphenyl 1                                                                     214 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 3,4-Methyl                                                             enedioxyphenyl 1                                                                215 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 2,3-Dihydr                                                             o-benzofuran-5-yl                                                              1                        216 OH p-Methylphenyl p-Methylphenyl Ethyl 2,3-Dihydro-1H-inden-5-yl 1                                                                217 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 3-Methoxy-                                                             5-methylphenyl 1                                                                218 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 3,4-Ethyle                                                             nedioxyphenyl 1                                                                 219 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 5-Methoxy-                                                             3,4-methylenedioxy                                                             phenyl 1                 220 OH p-Methylphenyl p-Methylphenyl Ethyl 3,5-Diethylphenyl 1                 221 OH p-Methylphenyl p-Methylphenyl Ethyl 3,4-Dimethoxyphenyl 1                                                                      222 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 3-Methyl-4                                                             -benzyloxyphenyl                                                               1                        223 OH p-Methylphenyl p-Methylphenyl Ethyl 3-Benzyloxy-5-methoxyphenyl                                                               1                        224 OH p-Methylphenyl p-Methylphenyl Ethyl 3-Benzyloxy-4-methoxyphenyl                                                               1                        225 OH p-Methylphenyl p-Methylphenyl Ethyl 3-Hydroxy-4-methoxyphenyl 1                                                                226 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 4-Hydroxy-                                                             3-methoxyphenyl 1        227 OH p-Methylphenyl p-Methylphenyl Ethyl 3,5-Bis-(trifluoromethyl)-phe                                                             nyl 1                    228 OH p-Methylphenyl p-Methylphenyl Ethyl 3-Methylphenyl 1                    229 OH p-Methylphenyl p-Methylphenyl Ethyl 3-Methoxyphenyl 1                   230 OH p-Methylphenyl p-Methylphenyl Ethyl 4-Benzyloxyphenyl 1                 231 OH p-Methylphenyl p-Methylphenyl Ethyl 4-Phenoxyphenyl 1                   232 OH p-Methylphenyl p-Methylphenyl Ethyl 6-Methylpyridin-2-yl 1                                                                     233 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 6-Ethylpyr                                                             idin-2-yl 1                                                                     234 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 6-Methoxyp                                                             yridin-2-yl 1                                                                   235 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 4,6-Dimeth                                                             ylpyridin-2-yl 1                                                                236 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 4,6-Diethy                                                             lpyridin-2-yl 1                                                                 237 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 4-Methyl-6                                                             -methoxypyridin-2-                                                             yl 1                     238 OH p-Methylphenyl p-Methylphenyl Ethyl 6,7-Dihydro-5H-cyclopenta[b]p                                                             yridin-2-yl 1                                                                   239 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 4,6-Dimeth                                                             ylpyrimidin-2-yl                                                               1                        240 OH p-Methylphenyl p-Methylphenyl Ethyl 4-Methoxy-6-methylpyrimidin-2                                                             -yl 1                    241 OH p-Methylphenyl p-Methylphenyl Ethyl 4,6-Dimethoxypyrimidin-2-yl                                                               1                        242 OH p-Methylphenyl p-Methylphenyl Ethyl 4,6-Diethylpyrimidin-2-yl 1                                                                243 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl 6,7-Dihydr                                                             o-5H-cyclopentapyr                                                             imidin-2-yl 1                                                                   244 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Ethyl Naphth-2-y                                                             l 1                      245 OH p-Methylphenyl p-Methylphenyl Ethyl 6,7-Dihydro-5H-cyclopenta[c]p                                                             yridin-2-yl 1                                                                   246 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   Phenyl 1                 247 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3,5-Dimet                                                             hylphenyl 1                                                                     248 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   3,5-Dimethoxypheny                                                             l 1                      249 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3,4-Methy                                                             lenedioxyphenyl 1        250 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 2,3-Dihyd                                                             ro-benzofuran-5-yl                                                              1                       251 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 2,3-Dihyd                                                             ro-1H-inden-5-yl                                                               1                        252 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Methoxy                                                             -5-methylphenyl 1        253 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3,4-Ethyl                                                             enedioxyphenyl 1                                                                254 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   5-Methoxy-3,4-meth                                                             ylenedioxyphenyl                                                               1                        255 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3,5-Dieth                                                             ylphenyl 1                                                                      256 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   3,4-Dimethoxypheny                                                             l 1                      257 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Methyl-                                                             4-benzyloxyphenyl                                                              1                        258 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Benzylo                                                             xy-5-methoxyphenyl                                                              1                       259 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Benzylo                                                             xy-4-methoxyphenyl                                                              1                       260 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Hydroxy                                                             -4-methoxyphenyl                                                               1                        261 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4-Hydroxy                                                             -3-methoxyphenyl                                                               1                        262 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3,5-Bis-(                                                             trifluoromethyl)-p                                                             henyl 1                  263 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Methylp                                                             henyl 1                  264 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 3-Methoxy                                                             phenyl 1                 265 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4-Benzylo                                                             xyphenyl 1                                                                      266 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   4-Phenoxyphenyl 1        267 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 6-Methylp                                                             yridin-2-yl 1                                                                   268 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   6-Ethylpyridin-2-y                                                             l 1                      269 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 6-Methoxy                                                             pyridin-2-yl 1                                                                  270 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   4,6-Dimethylpyridi                                                             n-2-yl 1                 271 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4,6-Dieth                                                             ylpyridin-2-yl 1                                                                272 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  273 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   274 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4,6-Dimet                                                             hylpyrimidin-2-yl                                                              1                        275 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4-Methoxy                                                             -6-methylpyrimidin                                                             -2-yl 1                  276 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4,6-Dimet                                                             hoxypyrimidin-2-yl                                                              1                       277 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 4,6-Dieth                                                             ylpyrimidin-2-yl                                                               1                        278 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Ethyl 6,7-Dihyd                                                             ro-5H-cyclopentapy                                                             rimidin-2-yl 1                                                                  279 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   Naphth-2-yl 1                                                                   280 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Ethyl                                                                   6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   281 OH Phenyl Phenyl Propyl Phenyl 1                                           282 OH Phenyl Phenyl Propyl 3,5-Dimethylphenyl 1                               283 OH Phenyl Phenyl Propyl 3,5-Dimethoxyphenyl 1                              284 OH Phenyl Phenyl Propyl 3,4-Methylenedioxyphenyl 1                         285 OH Phenyl Phenyl Propyl 2,3-Dihydro-benzofuran-5-yl 1                      286 OH Phenyl Phenyl Propyl 2,3-Dihydro-1H-inden-5-yl 1                        287 OH Phenyl Phenyl Propyl 3-Methoxy-5-methylphenyl 1                         288 OH Phenyl Phenyl Propyl 3,4-Ethylenedioxyphenyl 1                          289 OH Phenyl Phenyl Propyl 5-Methoxy-3,4-methylenedioxyphenyl 1                                                                      290 OH Phenyl                                                                 Phenyl Propyl                                                                  3,5-Diethylphenyl                                                              1                        291 OH Phenyl Phenyl Propyl 3,4-Dimethoxyphenyl 1                              292 OH Phenyl Phenyl Propyl 3-Methyl-4-benzyloxyphenyl 1                       293 OH Phenyl Phenyl Propyl 3-Benzyloxy-5-methoxyphenyl 1                      294 OH Phenyl Phenyl Propyl 3-Benzyloxy-4-methoxyphenyl 1                      295 OH Phenyl Phenyl Propyl 3-Hydroxy-4-methoxyphenyl 1                        296 OH Phenyl Phenyl Propyl 4-Hydroxy-3-methoxyphenyl 1                        297 OH Phenyl Phenyl Propyl 3,5-Bis-(trifluoromethyl)-phenyl 1                 298 OH Phenyl Phenyl Propyl 3-Methylphenyl 1                                   299 OH Phenyl Phenyl Propyl 3-Methoxyphenyl 1                                  300 OH Phenyl Phenyl Propyl 4-Benzyloxyphenyl 1                                301 OH Phenyl Phenyl Propyl 4-Phenoxyphenyl 1                                  302 OH Phenyl Phenyl Propyl 6-Methylpyridin-2-yl 1                             303 OH Phenyl Phenyl Propyl 6-Ethylpyridin-2-yl 1                              304 OH Phenyl Phenyl Propyl 6-Methoxypyridin-2-yl 1                            305 OH Phenyl Phenyl Propyl 4,6-Dimethylpyridin-2-yl 1                         306 OH Phenyl Phenyl Propyl 4,6-Diethylpyridin-2-yl 1                          307 OH Phenyl Phenyl Propyl 4-Methyl-6-methoxypyridin-2-yl 1                   308 OH Phenyl Phenyl Propyl 6,7-Dihydro-5H-cyclopenta[b]pyridin-2-yl 1                                                                309 OH Phenyl                                                                 Phenyl Propyl                                                                  4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                      310 OH Phenyl                                                                 Phenyl Propyl                                                                  4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                311 OH Phenyl                                                                 Phenyl Propyl                                                                  4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     312 OH Phenyl                                                                 Phenyl Propyl                                                                  4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       313 OH Phenyl                                                                 Phenyl Propyl                                                                  6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    314 OH Phenyl Phenyl Propyl Naphth-2-yl 1                                      315 OH Phenyl Phenyl Propyl 6,7-Dihydro-5H-cyclopenta[c]pyridin-2-yl 1                                                                316 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl Phenyl                                                              1                        317 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 3,5-Dimethylphenyl 1                                                                    318 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3,5-Dimethoxypheny                                                             l 1                      319 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 3,4-Methylenedioxyphenyl                                                               1                        320 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 2,3-Dihydro-benzofuran-5-y                                                             l 1                      321 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 2,3-Dihydro-1H-inden-5-yl                                                              1                        322 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 3-Methoxy-5-methylphenyl                                                               1                        323 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 3,4-Ethylenedioxyphenyl 1        324 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 5-Methoxy-3,4-methylenedio                                                             xyphenyl 1                                                                      325 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3,5-Diethylphenyl                                                              1                        326 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 3,4-Dimethoxyphenyl 1                                                                   327 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3-Methyl-4-benzylo                                                             xyphenyl 1                                                                      328 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3-Benzyloxy-5-meth                                                             oxyphenyl 1                                                                     329 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3-Benzyloxy-4-meth                                                             oxyphenyl 1                                                                     330 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3-Hydroxy-4-methox                                                             yphenyl 1                                                                       331 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     4-Hydroxy-3-methox                                                             yphenyl 1                                                                       332 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                333 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3-Methylphenyl 1                                                                334 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     3-Methoxyphenyl 1        335 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4-Benzyloxyphenyl 1                                                                     336 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     4-Phenoxyphenyl 1        337 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 6-Methylpyridin-2-yl 1                                                                  338 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     6-Ethylpyridin-2-y                                                             l 1                      339 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 6-Methoxypyridin-2-yl 1                                                                 340 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     4,6-Dimethylpyridi                                                             n-2-yl 1                 341 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4,6-Diethylpyridin-2-yl 1        342 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4-Methyl-6-methoxypyridin-                                                             2-yl 1                   343 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 6,7-Dihydro-5H-cyclopenta-                                                             [b]pyridin-2-yl 1        344 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4,6-Dimethylpyrimidin-2-yl                                                              1                       345 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4-Methoxy-6-methylpyrimidi                                                             n-2-yl 1                 346 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4,6-Dimethoxypyrimidin-2-y                                                             l 1                      347 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 4,6-Diethylpyrimidin-2-yl                                                              1                        348 OH p-Methoxyphenyl p-Methoxyphenyl Propyl 6,7-Dihydro-5H-cyclopentap                                                             yrimidin-2-yl 1                                                                 349 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     Naphth-2-yl 1                                                                   350 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl Propyl                                                                     6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   351 OH p-Methylphenyl p-Methylphenyl Propyl Phenyl 1                           352 OH p-Methylphenyl p-Methylphenyl Propyl 3,5-Dimethylphenyl 1                                                                      353 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 3,5-Dimet                                                             hoxyphenyl 1                                                                    354 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 3,4-Methy                                                             lenedioxyphenyl 1        355 OH p-Methylphenyl p-Methylphenyl Propyl 2,3-Dihydro-benzofuran-5-yl                                                              1                        356 OH p-Methylphenyl p-Methylphenyl Propyl 2,3-Dihydro-1H-inden-5-yl 1        357 OH p-Methylphenyl p-Methylphenyl Propyl 3-Methoxy-5-methylphenyl 1                                                                358 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 3,4-Ethyl                                                             enedioxyphenyl 1                                                                359 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 5-Methoxy                                                             -3,4-methylenediox                                                             yphenyl 1                                                                       360 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 3,5-Dieth                                                             ylphenyl 1                                                                      361 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 3,4-Dimet                                                             hoxyphenyl 1                                                                    362 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 3-Methyl-                                                             4-benzyloxyphenyl                                                              1                        363 OH p-Methylphenyl p-Methylphenyl Propyl 3-Benzyloxy-5-methoxyphenyl                                                              1                        364 OH p-Methylphenyl p-Methylphenyl Propyl 3-Benzyloxy-4-methoxyphenyl                                                              1                        365 OH p-Methylphenyl p-Methylphenyl Propyl 3-Hydroxy-4-methoxyphenyl 1        366 OH p-Methylphenyl p-Methylphenyl Propyl 4-Hydroxy-3-methoxyphenyl 1        367 OH p-Methylphenyl p-Methylphenyl Propyl 3,5-Bis-(trifluoromethyl)-ph                                                             enyl 1                   368 OH p-Methylphenyl p-Methylphenyl Propyl 3-Methylphenyl 1                   369 OH p-Methylphenyl p-Methylphenyl Propyl 3-Methoxyphenyl 1                  370 OH p-Methylphenyl p-Methylphenyl Propyl 4-Benzyloxyphenyl 1                                                                       371 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 4-Phenoxy                                                             phenyl 1                 372 OH p-Methylphenyl p-Methylphenyl Propyl 6-Methylpyridin-2-yl 1                                                                    373 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 6-Ethylpy                                                             ridin-2-yl 1                                                                    374 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 6-Methoxy                                                             pyridin-2-yl 1                                                                  375 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 4,6-Dimet                                                             hylpyridin-2-yl 1        376 OH p-Methylphenyl p-Methylphenyl Propyl 4,6-Diethylpyridin-2-yl 1                                                                 377 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 4-Methyl-                                                             6-methoxypyridin-2                                                             -yl 1                    378 OH p-Methylphenyl p-Methylphenyl Propyl 6,7-Dihydro-5H-cyclopenta[b]                                                             pyridin-2-yl 1                                                                  379 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl 4,6-Dimet                                                             hylpyrimidin-2-yl                                                              1                        380 OH p-Methylphenyl p-Methylphenyl Propyl 4-Methoxy-6-methylpyrimidin-                                                             2-yl 1                   381 OH p-Methylphenyl p-Methylphenyl Propyl 4,6-Dimethoxypyrimidin-2-yl                                                              1                        382 OH p-Methylphenyl p-Methylphenyl Propyl 4,6-Diethylpyrimidin-2-yl 1        383 OH p-Methylphenyl p-Methylphenyl Propyl 6,7-Dihydro-5H-cyclopentapyr                                                             imidin-2-yl 1                                                                   384 OH p-Methylph                                                             enyl p-Methylpheny                                                             l Propyl Naphth-2-                                                             yl 1                     385 OH p-Methylphenyl p-Methylphenyl Propyl 6,7-Dihydro-5H-cyclopenta[c]                                                             pyridin-2-yl 1                                                                  386 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  Phenyl 1                 387 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3,5-Dimethylphenyl                                                              1                       388 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3,5-Dimethoxypheny                                                             l 1                      389 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3,4-Methylenedioxy                                                             phenyl 1                 390 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      2,3-Dihydro-benzof                                                             uran-5-yl 1                                                                     391 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  2,3-Dihydro-1H-ind                                                             en-5-yl 1                                                                       392 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3-Methoxy-5-methyl                                                             phenyl 1                 393 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3,4-Ethylenedioxyp                                                             henyl 1                  394 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      5-Methoxy-3,4-meth                                                             ylenedioxyphenyl                                                               1                        395 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3,5-Diethylphenyl                                                              1                        396 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3,4-Dimethoxypheny                                                             l 1                      397 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      3-Methyl-4-benzylo                                                             xyphenyl 1                                                                      398 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3-Benzyloxy-5-meth                                                             oxyphenyl 1                                                                     399 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3-Benzyloxy-4-meth                                                             oxyphenyl 1                                                                     400 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3-Hydroxy-4-methox                                                             yphenyl 1                                                                       401 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  4-Hydroxy-3-methox                                                             yphenyl 1                                                                       402 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                403 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3-Methylphenyl 1                                                                404 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  3-Methoxyphenyl 1        405 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      4-Benzyloxyphenyl                                                              1                        406 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      4-Phenoxyphenyl 1        407 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      6-Methylpyridin-2-                                                             yl 1                     408 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      6-Ethylpyridin-2-y                                                             l 1                      409 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      6-Methoxypyridin-2                                                             -yl 1                    410 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      4,6-Dimethylpyridi                                                             n-2-yl 1                 411 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      4,6-Diethylpyridin                                                             -2-yl 1                  412 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  413 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   414 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                      415 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                416 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     417 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       418 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    419 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl Propyl                                                                      Naphth-2-yl 1                                                                   420 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl Propyl                                                                  6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   421 OH Phenyl Phenyl 2-Hydroxyethyl Phenyl 1                                   422 OH Phenyl Phenyl 2-Hydroxyethyl 3,5-Dimethylphenyl 1                       423 OH Phenyl Phenyl 2-Hydroxyethyl 3,5-Dimethoxyphenyl 1                      424 OH Phenyl Phenyl 2-Hydroxyethyl 3,4-Methylenedioxyphenyl 1                 425 OH Phenyl Phenyl 2-Hydroxyethyl 2,3-Dihydro-benzofuran-5-yl 1                                                                     426 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 2,3-Dihydro-1H                                                             -inden-5-yl 1                                                                   427 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 3-Methoxy-5-me                                                             thylphenyl 1                                                                    428 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 3,4-Ethylenedi                                                             oxyphenyl 1                                                                     429 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 5-Methoxy-3,4-                                                             methylenedioxyphen                                                             yl 1                     430 OH Phenyl Phenyl 2-Hydroxyethyl 3,5-Diethylphenyl 1                        431 OH Phenyl Phenyl 2-Hydroxyethyl 3,4-Dimethoxyphenyl 1                      432 OH Phenyl Phenyl 2-Hydroxyethyl 3-Methyl-4-benzyloxyphenyl 1                                                                      433 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 3-Benzyloxy-5-                                                             methoxyphenyl 1                                                                 434 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 3-Benzyloxy-4-                                                             methoxyphenyl 1                                                                 435 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 3-Hydroxy-4-me                                                             thoxyphenyl 1                                                                   436 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 4-Hydroxy-3-me                                                             thoxyphenyl 1                                                                   437 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 3,5-Bis-(trifl                                                             uoromethyl)-phenyl                                                              1                       438 OH Phenyl Phenyl 2-Hydroxyethyl 3-Methylphenyl 1                           439 OH Phenyl Phenyl 2-Hydroxyethyl 3-Methoxyphenyl 1                          440 OH Phenyl Phenyl 2-Hydroxyethyl 4-Benzyloxyphenyl 1                        441 OH Phenyl Phenyl 2-Hydroxyethyl 4-Phenoxyphenyl 1                          442 OH Phenyl Phenyl 2-Hydroxyethyl 6-Methylpyridin-2-yl 1                     443 OH Phenyl Phenyl 2-Hydroxyethyl 6-Ethylpyridin-2-yl 1                      444 OH Phenyl Phenyl 2-Hydroxyethyl 6-Methoxypyridin-2-yl 1                    445 OH Phenyl Phenyl 2-Hydroxyethyl 4,6-Dimethylpyridin-2-yl 1                 446 OH Phenyl Phenyl 2-Hydroxyethyl 4,6-Diethylpyridin-2-yl 1                  447 OH Phenyl Phenyl 2-Hydroxyethyl 4-Methyl-6-methoxypyridin-2-yl 1                                                                  448 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 6,7-Dihydro-5H                                                             -cyclopenta[b]pyri                                                             din-2-yl 1                                                                      449 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 4,6-Dimethylpy                                                             rimidin-2-yl 1                                                                  450 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 4-Methoxy-6-me                                                             thylpyrimidin-2-yl                                                              1                       451 OH Phenyl Phenyl 2-Hydroxyethyl 4,6-Dimethoxypyrimidin-2-yl 1                                                                     452 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 4,6-Diethylpyr                                                             imidin-2-yl 1                                                                   453 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl 6,7-Dihydro-5H                                                             -cyclopentapyrimid                                                             in-2-yl 1                                                                       454 OH Phenyl                                                                 Phenyl 2-Hydroxyet                                                             hyl Naphth-2-yl 1        455 OH Phenyl Phenyl 2-Hydroxyethyl 6,7-Dihydro-5H-cyclopenta[c]pyridin-                                                             2-yl 1                   456 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl Phenyl 1                 457 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3,5-Dimethylphenyl                                                              1                       458 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3,5-Dimethoxypheny                                                             l 1                      459 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3,4-Methylenedioxy                                                             phenyl 1                 460 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 2,3-Dihydro-benzof                                                             uran-5-yl 1                                                                     461 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              2,3-Dihydro-1H-in                                                             den-5-yl 1                                                                      462 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3-Methoxy-5-methy                                                             lphenyl 1                                                                       463 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3,4-Ethylenedioxy                                                             phenyl 1                 464 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 5-Methoxy-3,4-meth                                                             ylenedioxyphenyl                                                               1                        465 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3,5-Diethylphenyl                                                              1                        466 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3,4-Dimethoxypheny                                                             l 1                      467 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3-Methyl-4-benzylo                                                             xyphenyl 1                                                                      468 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3-Benzyloxy-5-met                                                             hoxyphenyl 1                                                                    469 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3-Benzyloxy-4-met                                                             hoxyphenyl 1                                                                    470 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3-Hydroxy-4-metho                                                             xyphenyl 1                                                                      471 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              4-Hydroxy-3-metho                                                             xyphenyl 1                                                                      472 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3,5-Bis-(trifluor                                                             omethyl)-phenyl 1        473 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 3-Methylphenyl 1                                                                474 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              3-Methoxyphenyl                                                               1                        475 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4-Benzyloxyphenyl                                                              1                        476 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4-Phenoxyphenyl 1        477 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 6-Methylpyridin-2-                                                             yl 1                     478 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 6-Ethylpyridin-2-y                                                             l 1                      479 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 6-Methoxypyridin-2                                                             -yl 1                    480 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4,6-Dimethylpyridi                                                             n-2-yl 1                 481 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4,6-Diethylpyridin                                                             -2-yl 1                  482 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  483 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              6,7-Dihydro-5H-cy                                                             clopenta[b]pyridin                                                             -2-yl 1                  484 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4,6-Dimethylpyrimi                                                             din-2-yl 1                                                                      485 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              4-Methoxy-6-methy                                                             lpyrimidin-2-yl 1        486 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl 4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     487 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              4,6-Diethylpyrimi                                                             din-2-yl 1                                                                      488 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              6,7-Dihydro-5H-cy                                                             clopentapyrimidin-                                                             2-yl 1                   489 OH p-Methoxyphenyl p-Methoxyphenyl 2-Hydroxyethyl Naphth-2-yl 1                                                                   490 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Hydroxyethyl                                                              6,7-Dihydro-5H-cy                                                             clopenta-[c]pyridi                                                             n-2-yl 1                 491 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl Phenyl 1                   492 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3,5-Dimethylphenyl                                                               1                        493 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3,5-Dimethoxyphenyl                                                              1                        494 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3,4-Methylenedioxyph                                                             enyl 1                   495 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 2,3-Dihydro-benzofur                                                             an-5-yl 1                                                                       496 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               2,3-Dihydro-1H-ind                                                             en-5-yl 1                                                                       497 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3-Methoxy-5-methyl                                                             phenyl 1                 498 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3,4-Ethylenedioxyphe                                                             nyl 1                    499 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 5-Methoxy-3,4-methyl                                                             enedioxyphenyl 1                                                                500 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3,5-Diethylphenyl                                                              1                        501 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3,4-Dimethoxyphenyl                                                              1                        502 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3-Methyl-4-benzyloxy                                                             phenyl 1                 503 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 3-Benzyloxy-5-methox                                                             yphenyl 1                                                                       504 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3-Benzyloxy-4-meth                                                             oxyphenyl 1                                                                     505 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3-Hydroxy-4-methox                                                             yphenyl 1                                                                       506 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               4-Hydroxy-3-methox                                                             yphenyl 1                                                                       507 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                508 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3-Methylphenyl 1                                                                509 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               3-Methoxyphenyl 1        510 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4-Benzyloxyphenyl 1        511 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4-Phenoxyphenyl 1                                                                 512 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               6-Methylpyridin-2-                                                             yl 1                     513 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 6-Ethylpyridin-2-yl                                                              1                        514 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 6-Methoxypyridin-2-y                                                             l 1                      515 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4,6-Dimethylpyridin-                                                             2-yl 1                   516 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4,6-Diethylpyridin-2                                                             -yl 1                    517 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4-Methyl-6-methoxypy                                                             ridin-2-yl 1                                                                    518 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   519 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4,6-Dimethylpyrimidi                                                             n-2-yl 1                 520 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl 4-Methoxy-6-methylpy                                                             rimidin-2-yl 1                                                                  521 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     522 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       523 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    524 OH p-Methylphenyl p-Methylphenyl 2-Hydroxyethyl Naphth-2-yl 1                                                                     525 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Hydroxyethyl                                                               6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   526 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              Phenyl 1                 527 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3,5-Dimethylphenyl                                                              1                       528 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3,5-Dimethoxypheny                                                             l 1                      529 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3,4-Methylenedioxy                                                             phenyl 1                 530 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              2,3-Dihydro-benzof                                                             uran-5-yl 1                                                                     531 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 2,3-Dihydro-1H                                                             -inden-5-yl 1                                                                   532 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3-Methoxy-5-me                                                             thylphenyl 1                                                                    533 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3,4-Ethylenedi                                                             oxyphenyl 1                                                                     534 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 5-Methoxy-3,4-                                                             methylenedioxyphen                                                             yl 1                     535 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3,5-Diethylphenyl                                                              1                        536 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3,4-Dimethoxypheny                                                             l 1                      537 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3-Methyl-4-benzylo                                                             xyphenyl 1                                                                      538 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3-Benzyloxy-5-                                                             methoxyphenyl 1                                                                 539 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3-Benzyloxy-4-                                                             methoxyphenyl 1                                                                 540 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3-Hydroxy-4-me                                                             thoxyphenyl 1                                                                   541 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 4-Hydroxy-3-me                                                             thoxyphenyl 1                                                                   542 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3,5-Bis-(trifl                                                             uoromethyl)-phenyl                                                              1                       543 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              3-Methylphenyl 1                                                                544 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 3-Methoxypheny                                                             l 1                      545 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              4-Benzyloxyphenyl                                                              1                        546 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              4-Phenoxyphenyl 1        547 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              6-Methylpyridin-2-                                                             yl 1                     548 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              6-Ethylpyridin-2-y                                                             l 1                      549 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              6-Methoxypyridin-2                                                             -yl 1                    550 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              4,6-Dimethylpyridi                                                             n-2-yl 1                 551 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              4,6-Diethylpyridin                                                             -2-yl 1                  552 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  553 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 6,7-Dihydro-5H                                                             -cyclopenta[b]pyri                                                             din-2-yl 1                                                                      554 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 4,6-Dimethylpy                                                             rimidin-2-yl 1                                                                  555 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 4-Methoxy-6-me                                                             thylpyrimidin-2-yl                                                              1                       556 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     557 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 4,6-Diethylpyr                                                             imidin-2-yl 1                                                                   558 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl 6,7-Dihydro-5H                                                             -cyclopentapyrimid                                                             in-2-yl 1                                                                       559 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Hydroxyet                                                             hyl Naphth-2-yl 1        560 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Hydroxyethyl                                                              6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   561 OH Phenyl Phenyl 2-Methylethyl Phenyl 1                                    562 OH Phenyl Phenyl 2-Methylethyl 3,5-Dimethylphenyl 1                        563 OH Phenyl Phenyl 2-Methylethyl 3,5-Dimethoxyphenyl 1                       564 OH Phenyl Phenyl 2-Methylethyl 3,4-Methylenedioxyphenyl 1                  565 OH Phenyl Phenyl 2-Methylethyl 2,3-Dihydro-benzofuran-5-yl 1                                                                      566 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 2,3-Dihydro-1H-                                                             inden-5-yl 1                                                                    567 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 3-Methoxy-5-met                                                             hylphenyl 1                                                                     568 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 3,4-Ethylenedio                                                             xyphenyl 1                                                                      569 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 5-Methoxy-3,4-m                                                             ethylenedioxypheny                                                             l 1                      570 OH Phenyl Phenyl 2-Methylethyl 3,5-Diethylphenyl 1                         571 OH Phenyl Phenyl 2-Methylethyl 3,4-Dimethoxyphenyl 1                       572 OH Phenyl Phenyl 2-Methylethyl 3-Methyl-4-benzyloxyphenyl 1                                                                       573 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 3-Benzyloxy-5-m                                                             ethoxyphenyl 1                                                                  574 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 3-Benzyloxy-4-m                                                             ethoxyphenyl 1                                                                  575 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 3-Hydroxy-4-met                                                             hoxyphenyl 1                                                                    576 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 4-Hydroxy-3-met                                                             hoxyphenyl 1                                                                    577 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 3,5-Bis-(triflu                                                             oromethyl)-phenyl                                                              1                        578 OH Phenyl Phenyl 2-Methylethyl 3-Methylphenyl 1                            579 OH Phenyl Phenyl 2-Methylethyl 3-Methoxyphenyl 1                           580 OH Phenyl Phenyl 2-Methylethyl 4-Benzyloxyphenyl 1                         581 OH Phenyl Phenyl 2-Methylethyl 4-Phenoxyphenyl 1                           582 OH Phenyl Phenyl 2-Methylethyl 6-Methylpyridin-2-yl 1                      583 OH Phenyl Phenyl 2-Methylethyl 6-Ethylpyridin-2-yl 1                       584 OH Phenyl Phenyl 2-Methylethyl 6-Methoxypyridin-2-yl 1                     585 OH Phenyl Phenyl 2-Methylethyl 4,6-Dimethylpyridin-2-yl 1                  586 OH Phenyl Phenyl 2-Methylethyl 4,6-Diethylpyridin-2-yl 1                   587 OH Phenyl Phenyl 2-Methylethyl 4-Methyl-6-methoxypyridin-2-yl 1                                                                   588 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 6,7-Dihydro-5H-                                                             cyclopenta[b]pyrid                                                             in-2-yl 1                                                                       589 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 4,6-Dimethylpyr                                                             imidin-2-yl 1                                                                   590 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 4-Methoxy-6-met                                                             hylpyrimidin-2-yl                                                              1                        591 OH Phenyl Phenyl 2-Methylethyl 4,6-Dimethoxypyrimidin-2-yl 1                                                                      592 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 4,6-Diethylpyri                                                             midin-2-yl 1                                                                    593 OH Phenyl                                                                 Phenyl 2-Methyleth                                                             yl 6,7-Dihydro-5H-                                                             cyclopentapyrimidi                                                             n-2-yl 1                 594 OH Phenyl Phenyl 2-Methylethyl Naphth-2-yl 1                               595 OH Phenyl Phenyl 2-Methylethyl 6,7-Dihydro-5H-cyclopenta[c]pyridin-2                                                             -yl 1                    596 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl Phenyl 1                  597 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3,5-Dimethylphenyl                                                              1                        598 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3,5-Dimethoxyphenyl                                                              1                       599 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3,4-Methylenedioxyp                                                             henyl 1                  600 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 2,3-Dihydro-benzofu                                                             ran-5-yl 1                                                                      601 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              2,3-Dihydro-1H-ind                                                             en-5-yl 1                                                                       602 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3-Methoxy-5-methyl                                                             phenyl 1                 603 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3,4-Ethylenedioxyph                                                             enyl 1                   604 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 5-Methoxy-3,4-methy                                                             lenedioxyphenyl 1        605 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3,5-Diethylphenyl                                                               1                        606 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3,4-Dimethoxyphenyl                                                              1                       607 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 3-Methyl-4-benzylox                                                             yphenyl 1                                                                       608 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3-Benzyloxy-5-meth                                                             oxyphenyl 1                                                                     609 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3-Benzyloxy-4-meth                                                             oxyphenyl 1                                                                     610 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3-Hydroxy-4-methox                                                             yphenyl 1                                                                       611 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              4-Hydroxy-3-methox                                                             yphenyl 1                                                                       612 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                613 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3-Methylphenyl 1                                                                614 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              3-Methoxyphenyl 1        615 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 4-Benzyloxyphenyl                                                               1                        616 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 4-Phenoxyphenyl 1                                                                617 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              6-Methylpyridin-2-                                                             yl 1                     618 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 6-Ethylpyridin-2-yl                                                              1                       619 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 6-Methoxypyridin-2-                                                             yl 1                     620 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 4,6-Dimethylpyridin                                                             -2-yl 1                  621 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 4,6-Diethylpyridin-                                                             2-yl 1                   622 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 4-Methyl-6-methoxyp                                                             yridin-2-yl 1                                                                   623 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   624 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl 4,6-Dimethylpyrimid                                                             in-2-yl 1                                                                       625 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              4-Methoxy-6-methyl                                                             pyrimidin-2-yl 1                                                                626 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     627 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       628 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    629 OH p-Methoxyphenyl p-Methoxyphenyl 2-Methylethyl Naphth-2-yl 1                                                                    630 OH p-Methoxyp                                                             henyl p-Methoxyphe                                                             nyl 2-Methylethyl                                                              6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   631 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl Phenyl 1                    632 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3,5-Dimethylphenyl 1        633 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3,5-Dimethoxyphenyl                                                               1                        634 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3,4-Methylenedioxyphe                                                             nyl 1                    635 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 2,3-Dihydro-benzofura                                                             n-5-yl 1                 636 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 2,3-Dihydro-1H-inden-                                                             5-yl 1                   637 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3-Methoxy-5-methylphe                                                             nyl 1                    638 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3,4-Ethylenedioxyphen                                                             yl 1                     639 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 5-Methoxy-3,4-methyle                                                             nedioxyphenyl 1                                                                 640 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                3,5-Diethylphenyl                                                              1                        641 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3,4-Dimethoxyphenyl                                                               1                        642 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3-Methyl-4-benzyloxyp                                                             henyl 1                  643 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3-Benzyloxy-5-methoxy                                                             phenyl 1                 644 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3-Benzyloxy-4-methoxy                                                             phenyl 1                 645 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3-Hydroxy-4-methoxyph                                                             enyl 1                   646 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4-Hydroxy-3-methoxyph                                                             enyl 1                   647 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 3,5-Bis-(trifluoromet                                                             hyl)-phenyl 1                                                                   648 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                3,5-Bis-(trifluoro                                                             methyl)-phenyl 1                                                                649 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                3-Methoxyphenyl 1        650 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4-Benzyloxyphenyl 1                                                                651 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                4-Phenoxyphenyl 1        652 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 6-Methylpyridin-2-yl                                                              1                        653 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 6-Ethylpyridin-2-yl                                                               1                        654 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 6-Methoxypyridin-2-yl                                                              1                       655 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4,6-Dimethylpyridin-2                                                             -yl 1                    656 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4,6-Diethylpyridin-2-                                                             yl 1                     657 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4-Methyl-6-methoxypyr                                                             idin-2-yl 1                                                                     658 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                6,7-Dihydro-5H-cyc                                                             lopenta[b]pyridin-                                                             2-yl 1                   659 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4,6-Dimethylpyrimidin                                                             -2-yl 1                  660 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl 4-Methoxy-6-methylpyr                                                             imidin-2-yl 1                                                                   661 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     662 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                4,6-Diethylpyrimid                                                             in-2-yl 1                                                                       663 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                6,7-Dihydro-5H-cyc                                                             lopentapyrimidin-2                                                             -yl 1                    664 OH p-Methylphenyl p-Methylphenyl 2-Methylethyl Naphth-2-yl 1                                                                      665 OH p-Methylph                                                             enyl p-Methylpheny                                                             l 2-Methylethyl                                                                6,7-Dihydro-5H-cyc                                                             lopenta[c]pyridin-                                                             2-yl 1                   666 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               Phenyl 1                 667 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3,5-Dimethylphenyl                                                              1                       668 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3,5-Dimethoxypheny                                                             l 1                      669 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3,4-Methylenedioxy                                                             phenyl 1                 670 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               2,3-Dihydro-benzof                                                             uran-5-yl 1                                                                     671 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 2,3-Dihydro-1H-                                                             inden-5-yl 1                                                                    672 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3-Methoxy-5-met                                                             hylphenyl 1                                                                     673 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3,4-Ethylenedio                                                             xyphenyl 1                                                                      674 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 5-Methoxy-3,4-m                                                             ethylenedioxypheny                                                             l 1                      675 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3,5-Diethylphenyl                                                              1                        676 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3,4-Dimethoxypheny                                                             l 1                      677 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3-Methyl-4-benzylo                                                             xyphenyl 1                                                                      678 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3-Benzyloxy-5-m                                                             ethoxyphenyl 1                                                                  679 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3-Benzyloxy-4-m                                                             ethoxyphenyl 1                                                                  680 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3-Hydroxy-4-met                                                             hoxyphenyl 1                                                                    681 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 4-Hydroxy-3-met                                                             hoxyphenyl 1                                                                    682 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3,5-Bis-(triflu                                                             oromethyl)-phenyl                                                              1                        683 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               3-Methylphenyl 1                                                                684 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 3-Methoxyphenyl                                                              1                       685 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               4-Benzyloxyphenyl                                                              1                        686 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               4-Phenoxyphenyl 1        687 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               6-Methylpyridin-2-                                                             yl 1                     688 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               6-Ethylpyridin-2-y                                                             l 1                      689 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               6-Methoxypyridin-2                                                             -yl 1                    690 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               4,6-Dimethylpyridi                                                             n-2-yl 1                 691 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               4,6-Diethylpyridin                                                             -2-yl 1                  692 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               4-Methyl-6-methoxy                                                             pyridin-2-yl 1                                                                  693 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 6,7-Dihydro-5H-                                                             cyclopenta[b]pyrid                                                             in-2-yl 1                                                                       694 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 4,6-Dimethylpyr                                                             imidin-2-yl 1                                                                   695 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 4-Methoxy-6-met                                                             hylpyrimidin-2-yl                                                              1                        696 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               4,6-Dimethoxypyrim                                                             idin-2-yl 1                                                                     697 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 4,6-Diethylpyri                                                             midin-2-yl 1                                                                    698 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 6,7-Dihydro-5H-                                                             cyclopentapyrimidi                                                             n-2-yl 1                 699 OH 4-Methoxy-3-methylphenyl 4-Methoxy-3-methylphenyl 2-Methylethyl                                                               Naphth-2-yl 1                                                                   700 OH 4-Methoxy-                                                             3-methylphenyl                                                                 4-Methoxy-3-methyl                                                             phenyl 2-Methyleth                                                             yl 6,7-Dihydro-5H-                                                             cyclopenta[c]pyrid                                                             in-2-yl 1              __________________________________________________________________________

The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, kidney failure caused by ischemia and by intoxication, and hypertension.

The good effect of the compounds can be shown in the following tests:

Receptor-Binding Studies

Cloned human ET_(A) receptor-expressing CHO cells and guinea pig cerebellar membranes with >60% ETB receptors by comparison with ET_(A) receptors were employed for binding studies.

Membrane Preparation

The ET_(A) receptor-expressing CHO cells were grown in F₁₂ medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Then neutralization was carried out with F₁₂ medium, and the cells were collected by centrifugation at 300×g. To lyse the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 10⁷ cells/ml of lysis buffer at 4°-C. for 30 min. The membranes were centrifuged at 20,000×g for 10 min, and the pellet was stored in liquid nitrogen.

Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizer and obtained by differential centrifugation at 1,000×g for 10 min and repeated centrifugation of the supernatant at 20,000×g for 10 min.

Binding Assays

For the ET_(A) and ET_(B) receptor binding assay, the membranes were suspended in an incubation buffer (50 mM tris-HCl, pH 7.4, with 5 mM MnCl₂, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per assay mixture and incubated in the presence and absence of test substance with 25 pM ¹²⁵ I-ET₁ (ET_(A) receptor assay) or 25 pM ¹²⁵ -RZ₃ (ETB receptor assay) at 25° C. The nonspecific binding was determined with 10⁻⁷ M ET₁. After 30 min, the free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway), and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional in vitro assay system for searching for endothelin receptor (subtype A) antagonists

This assay system is a functional, cell-based assay for endothelin receptors. Certain cells show, when they are stimulated with endothelin 1 (ET1), an increase in the intracellular calcium concentration. This increase can be measured in intact cells which have been loaded with calcium-sensitive dyes.

1-Fibroblasts which were isolated from rats and in which an endogenous endothelin receptor of the A subtype had been detected were loaded with the fluorescent dye Fura 2-an as follows: after tripysinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCL, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM Glucose, pH 7.4) to a density of 2×10⁶ /ml and incubated with Fura-2-am (2 μM), Pluronic F-127 (0.04%) and DMSO (0.2%) at 37° C. in the dark for 30 min. The cells were then washed twice with buffer A and resuspended at 2×10⁶ /ml.

The fluorescence signal from 2×10⁵ cells per ml with Ex/Em 380/510 was recorded continuously at 30° C. The test substances and, after an incubation time of 3 min, ET1 were added to the cells. The maximum change in the fluorescence was determined over 30 min. The response of the cells to ET1 without previous addition of a test substance served as control and was set equal to 100%.

In Vivo Testing of ET Antagonists

Male SD rats weighting 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and the jugular vein were catheterized.

Intravenous administration of 1 μg/kg ET1 to control animals leads to a distinct rise in blood pressure which persists for a lengthy period.

The test compounds was [sic] injected i.v. (1 ml/kg) into the test animals 5 or 30 min before ET1 administration. To determine the ET-antagonistic properties, the increase in blood pressure in the test animals was compared with that in the control animals.

Endothelin-1 Induced Sudden Death in Mice

The principle of the test comprises the inhibition of the sudden heart death in mice which is caused by endothelin, probably due to constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight results in death of the animals within a few minutes.

The lethal endothelin-1 dose is checked in each case on a small group of animals. If the test substance is administered intravenously, it is usually followed after 5 min by the endothelin-1 injection which was lethal in the reference group. With other modes of administration, the times before administration are longer, where appropriate up to several hours.

The survival rate is recorded and effective doses which protect 50% of the animals for 24 h or longer against endothelin-induced heart death (ED 50) are determined.

Functional Test for Endothelin Receptor Antagonists on Vessels

Segments of rabbit aorta with an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37° C. and at a pH of from 7.3 to 7.4 are initially induced to contract with K⁺. After washing out, an endothelin dose-effect plot is constructed up to the maximum.

Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of endothelin are calculated as a % of the K⁺ contraction. Effective endothelin antagonists result in a shift in the endothelin dose-effect plot to the right.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of agent is about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The agents can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of the agent.

SYNTHETIC EXAMPLES Example 1 3,3-Bis(4-methoxyphenyl)butanoic acid

a) Ethyl (2E,Z)-3-(4-methoxyphenyl)-2-butenoate (6.6 g, 30 mmol) were dissolved in anisole (4.9 g, 45 mmol) at 0° C., and 50 ml of 80% H2SO₄ were cautiously added. The 2-phase mixture was vigorously stirred at room temperature for 20 h and then poured onto ice, and the product was extracted with ethyl acetate. The organic phase was dried (Na₂ SO₄), filtered and concentrated, the residue was taken up with ether and extracted with 2N sodium hydroxide solution, and the ether phase was discarded. The alkaline phase was adjusted to pH 2 with 2N HCl, and the product was extracted with ethyl acetate. The organic phase was then dried (Na₂ SO₄), filtered and concentrated, and the solid residue was stirred with diisopropyl ether. The product was filtered off with suction and dried. 5.1 g of a white powder (56%) remained.

Melting point: 161-164° C.

Further working up of the mother liquor was possible, resulting in a further 1.1 g (12%) of the acid.

The acid can also be prepared by the following alternative:

b) At 0° C., 32 ml of anisole (294 mmol) were mixed with 33 ml of ethyl acetoacetate (258 mmol), 150 ml of 70% H₂ SO₄ were cautiously added, and the resulting 2-phase mixture was vigorously stirred at room temperature for 72 h. The mixture was then poured onto ice and worked up further as under 1a). The residue was recrystallized from diisopropyl ether. 15.3 g (35%) of white solid remained.

c) Similar to the preparation of 3,3-diphenylbutanoic acid (Examples 3, 4)

Example 2 (2R, S)-3,3-Bis-(4-methoxyphenyl)-2-(3', 4'-methylenedioxybenzyl)-butanoic acid

Butyllithium (13.8 ml, 22 mmol, 1.6M in hexane) was added to a solution of diisopropylamine (3.1 ml, 22 mmol) in 50 ml of dry tetrahydrofuran under nitrogen at -10° C., the mixture was stirred at -10° C. for 5 min and then, at 0° C., 3,3-bis(4-methoxyphenyl)butanoic acid (3.0 g, 10 mmol) in 15 ml of absolute THF was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h, cooled to -20° C, and, after addition of piperonyl bromide (2.6 g, 12 mmol) in 10 ml of THF, stirred at room temperature for 72 h. The mixture was then quenched with saturated NH₄ Cl solution, the organic phase was separated off and the aqueous was extracted with ethyl acetate. The combined organic extracts were dried (Na₂ SO₄), filtered and concentrated in a rotary evaporator. The brown residue was chromatographed on silica gel (methanol/CH₂ Cl₂ 1:19), resulting in 1.3 g (30%) of product as a white foam.

Melting point: 137-140° C. (from diisopropyl ether)

Example 3 Ethyl 3,3-diphenylbutanoate

At 0° C., 65 g of AlCl₃ (487 mmol) were suspended in 500 ml of benzene, and 61.7 g of ethyl (2E,Z)-3-phenyl-2-butenoate were slowly added. The dark red solution was stirred at room temperature for 20 h and then poured into a mixture of ice and concentrated HCl. The organic phase was separated off, and the aqueous was extracted with ethyl acetate. The combined organic phases were extracted with NaOH and then dried (Na₂ SO₄), filtered and concentrated (66.8 g of dark brown oil).

56.5 g of this oil were distilled, resulting in 46.3 g of product as a colorless oil.

Example 4 5 3,3-Diphenylbutanoic acid

4.9 g of ethyl 3,3-diphenylbutanoate (18.3 mmol) were dissolved in 30 ml of dioxane, 36 ml of 1M KOH were added, and the mixture was stirred at 60-70° C. for 6 h.

The dioxane was then stripped off in a rotary evaporator, and the aqueous residue was diluted with water and extracted with diethyl ether. The aqueous phase was then adjusted to pH 1 and extracted with ethyl acetate. The organic phase was dried (Na₂ SO₄), filtered and concentrated. The solid residue was stirred with heptane, resulting in 2.35 g of a white powder (55%). The mother liquor was not purified further.

Example 5 (2R,S)-3,3-Diphenyl-2-(3', 4'-methylenedioxybenzyl)butanoic acid

15 ml of butyllithium (24 mmol, 1.6M in hexane) were added dropwise to a solution of 3,3-diphenylbutanoic acid (2,4 g, 10 mmol) in 40 ml of absolute THF at -20° C., and the mixture was then stirred at from -10 to -20° C. for 1 h. Then piperonyl chloride (2,2 g, 13 mmol) in 10 ml of THF was added, and the mixture was stirred at room temperature for 16 h and then quenched with saturated NH₄ Cl solution. The organic phase was separated off, the aqueous phase was extracted with ethyl acetate, and then the combined organic extracts were dried (Na₂ SO₄), filtered and concentrated. The residue was chromatographed on silica gel (CH₂ Cl₂ /MeOH 19:1), resulting in 2.4 g of the reqired product (65%).

The acid was dissolved in CH₂ Cl₂ and shaken with saturated sodium carbonate solution. The organic (I) phase was separated off, dried (Na₂ SO₄), filtered and concentrated. 2.5 g of sodium salt of the acid were obtained.

Melting point: 308-310° C. (decomposition)

Example 6 3,3-Bis(4-methoxy-3-methylphenyl)butanoic acid

Preparation took place as in Example 1b. However, in this case, mainly the corresponding ethyl ester was isolated so that subsequent hydrolysis was necessary (as in Example 4).

Melting point: 121-124° C.

Example 7 (2R,S)-3,3-Bis(4-methoxy-3-methylphenyl)-2-(3', 4'-methylenedioxy-benzyl) butanoic acid

Preparation similar to Example 2. 3.25 ml of diisopropylamine (23 mmol), 15.6 ml of butyllithium (23 mmol, 1.5 M in hexane), 3.28 g of 3,3-bis(4-methoxy-3-methylphenyl)butanoic acid (10 mmol), 2.19 g of piperonyl chloride (13 mmol) afford 4.1 g of crude product. Chromatography on silica gel (CH₂ Cl₂ /MeOH 19:1) afforded 1.6 g of product (35%)

Melting point: 152-153° C.

Example 8 (2R,S)-3,3-Diphenyl-2-(3', 4'-dimethoxybenzyl)butanoic acid

Preparation took place as in Example 5. 2.4 g of 3,3-diphenylbutanoic acid (10 mmol), 15.6 ml of butyllithium (23 mmol, 1.5 M in hexane), 2.2 g of 3,4-dimethoxybenzyl chloride (13 mmol) afforded 3.8 g of crude product. Purification on silica gel (heptane/ethyl acetate 1:1) 2.1 g of product (54%)

Melting point: 141-143° C.

Example 9 3,3-Bis(4-methoxyphenyl)pentanoic acid

Ethyl (2E,Z)-3-(4-methoxyphenyl)-2-pentenoate (7.0 g, 30 mmol) was dissolved in anisole (4.9 g, 45 mmol) at 0° C., and 50 ml of 80% H₂ SO₄ were cautiously added. The 2-phase mixture was vigorously 30 stirred at room temperature for 30 h and then poured onto ice, and the product was extracted with methylene chloride. The organic phase was dried (Na₂ SO₄), filtered and concentrated, the residue was taken up in ether and extracted with 2 N sodium hydroxide solution, and the ether phase was discarded. The alkaline phase was adjusted to pH 2 with 2N HCl, and the product was extracted with ethyl acetate. The organic phase was then dried (Na₂ SO₄), filtered and concentrated, and the solid residue was stirred with heptane. The product was filtered off with suction and dried. 6.8 g of a white powder (72%) remained.

Melting point: 136-139° C.

Example 10 (2R,S)-3,3-Bis(4-methoxyphenyl)pentanoic acid

29 ml of butyllithium (46 mmol, 1.6 M in hexane) were added dropwise to a solution of 3,3-bis(4-methoxyphenyl)pentanoic acid (6.2 g, 20 mmol) in 100 ml of absolute THF at -20° C., and the mixture was then stirred at room temperature for 1 h. Then, at -10° C., piperonyl chloride (4.4 g, 24 mmol) in 10 ml of THF was added, and the mixture was stirred at room temperature for 72 h and then quenched with saturated NH₄ Cl solution. The organic phase was separated off, the aqueous phase was extracted with ethyl acetate, and then the combined organic extracts were dried (Na₂ SO₄), filtered and concentrated. The residue (11.2 g) was chromatographed on silica gel (CH₂ Cl₂ /MeOH 24:1), resulting in 3.1 g of the required product (34%).

Melting point: 84-86° C. (stirred in heptane)

Example 11 Methyl 3,3-Bis(4-methoxyphenyl)hexanoate

Anisole (6.6 g, 61 mmol) was dissolved in 200 ml of dichloroethane and, at 0 C, aluminum trichloride (12,3 g, 92 mmol) was added in portions and subsequently, while stirring, methyl (2E,Z)-3-(4-methoxyphenyl)-2-hexenoate (18 g, 61 mmol) was added dropwise. The reaction mixture was stirred at 5° C. for 2 h and then at room temperature for 2 days. For workup, the mixture was poured into ice-water and extracted with CH₂ Cl₂, and the combined organic phases were washed with saturated NaCl solution and dried over MgSO₄. The residue remaining after concentration was purified by chromatography on silica gel (n-heptane/7.5% ethyl acetate). This resulted in 5.2 g (25%) of a colorless oil.

¹ H-NMR (CDCl₃), δ: 0.9 (m, 3H), 1.1 and 2.2 (each m, 2H), 3.08 (s, 2H), 3.4 (s, 3H) (s, 6H), 6.8 and 7.1 (each m, 4H) ppm.

Example 12 3,3-Bis(4-methoxyphenyl)hexanoic acid

Methyl 3,3-bis(4-methoxyphenyl)hexanoate (5.2 g, 15.2 mmol) was introduced into 20 ml of dioxane, KOH (1.05 g, 18.2 mmol) was added, and the mixture was boiled for about 1 h. It was subsequently diluted with water and washed with ethyl acetate, and the aqueous phase was then adjusted to pH 3 with dilute HCl and extracted with ethyl acetate. The organic phase was then washed with saturated NaCl solution, dried over MgSO₄ and concentrated. Chromatography on silica gel (CH₂ Cl₂ /methanol 3%) resulted in 4.1 g of a pale yellowish oil (84%).

¹ H-NMR (CDCl₃), δ: 0.9 (m, 3H), 1.1 und 2.2 (each m, 2H), 3.1 (s, 3H), 3.8 (s, 6H), 6.8 and 7.1 (each m, 4H) ppm.

Example 13

The following compounds were prepared as in Example 5.

(2R,S)-3,3-Diphenyl-2-(methyl-2'-naphthyl )butanoic acid Melting point: 163-164° C. FAB-MS: 380 (M⁺)

(2R,S)-3,3-Diphenyl-2-s(3', 5'-dimethylbenzyl)butanoic acid Melting point: 141-143° C. FAB-MS: 358 (M⁺)

(2R,S)-3,3-Diphenyl-2- (4'-benzyloxy-3-methoxybenzyl)butanoic acid Melting point: 163-166° C. FAB-MS: 466 (M⁺)

(2R,S)-3,3-Bis(4- methoxyphenyl)-2-(4-benzyloxy-3-methoxybenzyl )-butanoic acid Melting point: 137-140° C. FAB-MS: 526 (M⁺)

(2R,S)-3,3-Diphenyl-2-(4'-hydroxy-3'-methoxybenzyl)butanoic acid Melting point: 153-155° C. FAB-MS: 376 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(4'-hydroxy-3-methoxybenzyl)butanoic acid Melting point: 157-160° C. FAB-MS: 436 (M⁺)

(2R,S)-3,3-Bis(4-methoxy-3-methylphenyl)-2-(3', 5'-dimethyl-benzyl) butanoic acid Melting point: 150-152° C. FAB-MS: 446 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl )2--2-methyl-21-naphthyl)butanoic acid Melting point: 162-164° C. FAB-MS: 440 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 5'-dimethylbenzyl)butanoic acid Melting point: 125-128° C. FAB-MS: 418 (M⁺)

(2R,S)-3,3-Bis(4-methoxy-3-methylphenyl)-2-(3', 4'-dimethoxy-benzyl) butanoic acid Melting point: 155-157° C. FAB-MS: 478 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 4'-dimethoxybenzyl)butanoic acid Melting point: 148-150° C. FAB-MS: 450 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(5'-methoxy-3', 4'-methylene-dioxybenzyl) pentanoic acid Melting point: 138-141° C. FAB-MS: 478 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(5-methoxy-3', 4'-methylene-dioxybenzyl) butanoic acid Melting point: 134-136° C. FAB-MS: 464 (M⁺)

(2R,S)-3,3-Diphenyl-2-(5'-methoxy-3', 4'-methylenedioxybenzyl)-butanoic acid Melting point: 135-138° C. FAB-MS: 464 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 4'-ethylenedioxybenzyl)-pentanoic acid Melting point: 168-170° C. FAB-MS: 462 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 4'-ethylenedioxybenzyl)-butanoic acid Melting point: 161-163° C. FAB-MS: 448 (M⁺)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 4'-methylenedioxybenzyl)-hexanoic acid Melting point: 142-145° C. (from n-heptane)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 4'-ethylenedioxybenzyl)-hexanoic acid Melting point: 163-165° C. (from n-heptane/diethyl ether)

(2R,S)-3,3-Bis(4-methoxyphenyl)-2-(3', 4'-methylenedioxy-5'-methoxybenzyl) hexanoic acid Melting point: 180-182° C. (from n-heptane/diethyl ether)

Example 14

The compounds prepared in Examples 2 to 10 were checked for their endothelin receptor affinity by the methods described above. A compound disclosed in WO 94/02474 was used as comparison substance. The result is reported in the following Table.

    ______________________________________                                                               ET.sub.A                                                                             ET.sub.B                                           ______________________________________                                                                           420 nM #                                                                     >6400 nM                                          -                                                                                                              38 nM  2800 nM                                 -                                                                                                              6 nM  1300 nM                               ______________________________________                                     

We claim:
 1. A carboxylic acid derivative of the formula I ##STR24## where R¹ is a tetrazolyl radical, a cyanide radical, COOH or a radical which can be hydrolyzed to --COOH and;R² and R³, arephenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, cyano, NO₂, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino benzyloxy, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino; or phenyl or naphthyl which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethylene group, or an oxygen or sulfur atom; R⁴ is phenyl or naphthyl, methylenedioxyphenyl, ethylenedioxyphenyl, indanyl, indolyl, pyridyl, benzopyranyl, furanyl, pyrimidinyl, benzofuranyl, isooxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, C₃ -C₇ -cycloalkyl, thienyl, oxazolyl, thiazolyl, each of which are unsubstituted or optionally substituted by one or more of the following radicals: halogen, cyano, hydroxyl, NO₂, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino benzyloxy, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino, it being possible for the alkyl radicals together to form a ring; R⁵ is C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl, each of which are unsubstituted or optionally substituted one or more times by: halogen, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino; phenyl, benzyl, 1-methylnaphthyl, 2-methylnaphthyl or naphthyl, each of which are unsubstituted or optionally substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, phenoxy, C₁ -C₄ -alkylthio, dioxomethyl or dioxoethyl.
 2. A pharmaceutical composition comprising the carboxylic acid derivative defined in claim 1, and a pharmaceutically acceptable carrier.
 3. A method of treating hypertension or acute myocardial infaction, which method comprises administering to a mammal an effective amount of the composition defined in claim
 2. 